Gonadal neuroendocrine function is a key aspect of sex differences implicated in addiction. Focusing on the menstrual cycle and ovarian hormone modulation of nicotine's effects may elucidate etiologic mechanisms and neuroendocrine-based treatments for addiction among women and perhaps men also. Accordingly, this project tests a novel theoretical model which proposes that behavioral inhibition-a biobehavioral process that putatively influences addictive behavior, is modulated by nicotine, and is affected by ovarian hormones-is a mechanism linking neuroendocrine variation driven by the menstrual cycle and smoking in women. Behavioral inhibition refers to the ability to suppress habitual responses that are not required or appropriate in a given situation, which may be an important process that: (a) prevents compulsive drug use behavior among individuals not wishing to quit; and (b) promotes efforts to abstain during a cessation attempt. This model purports that poor behavioral inhibition during acute tobacco abstinence may be amplified during the menstrual cycle's late follicular phase (LF) when estrogen levels are high and unopposed by progesterone. By contrast, impaired behavioral inhibition during abstinence may be less pronounced during the mid-luteal phase (ML; when estrogen levels are moderate but are opposed by high progesterone levels) and the early follicular phase (EF; when both estrogen and progesterone are low; hormonal baseline). Nicotine may offset impaired behavioral inhibition caused by tobacco abstinence, particularly during the LF phase when behavioral inhibition deficits may be most pronounced. We will test this model in a placebo-controlled double-blind lab experiment with 80 non-treatment-seeking pre-menopausal female daily cigarette smokers. Females will complete three experimental visits (EF, LF, and ML) following 16-hr tobacco abstinence. During each visit, they will complete computer-based measures of behavioral inhibition at two time points during the session: (1) at the outset of the visit; and (2) following administration of transdermal patch. Thi study uses a mixed 2 (Between-Subject: Nicotine vs. Placebo) x3 (Within-Subject: Menstrual Cycle Phase) x2 (Within-Subject: Pre vs. Post Nicotine) factorial design. The primary aim of this study is to test the hypotheses that in the LF phase, as compared to the EF and ML phases, women will exhibit: (1) lower pre-nicotine behavioral inhibition and (2) higher nicotine-induced enhancement (Post - Pre nicotine) of behavioral inhibition. The secondary aim is to examine relations of phase-related changes in estrogen and progesterone levels to phase-related changes in behavioral inhibition to shed light on neuroendocrine pathways that underlie menstrual cycle and nicotine interactions. This project will pave the way for a program of research involving more intensive laboratory and clinical studies of neuroendocrine, pharmacological, and cognitive underpinnings of smoking and perhaps other addictions in women, with the ultimate aim of improving addiction treatment among women and across both sexes.